Recent observations have refuted the simplistic notion that females are immunologically unaware of the presence and activities of allogeneic cells and tissues within their reproductive tracts. This evidence allows us to conclude that active immunological responses on the part of the female following early recognitive events during pregnancy play an essential role in conferring selective benefits on the fetoplacental unit from the time of implantation to parturition. During mating, implantation, placentation, and througout gestation, fetal and histocompatibility antigens are presented to the mother in a unique manner. She does respond to these antigens and her responses aid in the establishment and maintenance of a harmonious state of immunological coexistence with her fetus. These maternal immunological responses are under strict genetic control by genes associated with the major histocompatibility complex which code for cell surface molecules present on all nucleated cells of the body. Antigens dictated by alleles at these loci, i.e., HLA-A, B, C, and D/DR, are recognized serologically and have been studied in couples with reporductive inefficiency. In addition, the immune responsiveness of the female to paternal antigens has been studied using the one-way mixed lymphocyte culture (MLC) system. Pilot studies currently underway in our laboratory in couples experiencing chronic habitual abortion of karyotypically normal fetuses and having no other medical or genetic abnormalities have shown that 1) these patients generally do not develop antileukocyte antibodies as a result of unsuccessful pregnancies, 2) these couples share a greater number of MHC antigens than control couples, and 3) D/DR locus compatibility is suggested not only by DR locus typing but also by hyporesponsiveness on the part of the female to presentation of paternal antigens in one-way mixed lymphocyte culture. We propose to expand these preliminary studies to include normal pregnancy controls and to assess the production of MLC blocking factor in spontaneous abortion. In addition, continuation of our leukocyte immunization program should allow us to assess the effectiveness of this treatment and provide further evidence with regard to the participation of the immune system in pregnancy.